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PDBsum entry 1jag

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1jag
Jmol
Contents
Protein chains
(+ 2 more) 229 a.a.
Ligands
ATP ×8
Waters ×200
Superseded by: 2ocp
PDB id:
1jag
Name: Transferase
Title: Crystal structure of human deoxyguanosine kinase
Structure: Deoxyguanosine kinase. Chain: a, b, c, d, e, f, g, h. Engineered: yes
Source: Homo sapiens. Human. Expressed in: escherichia coli.
Biol. unit: Dimer (from PQS)
Resolution:
2.80Å     R-factor:   0.265     R-free:   0.277
Authors: K.Johansson,S.Ramaswamy,C.Ljungkrantz,W.Knecht,J.Piskur, B.Munch-Petersen,S.Eriksson,H.Eklund
Key ref:
K.Johansson et al. (2001). Structural basis for substrate specificities of cellular deoxyribonucleoside kinases. Nat Struct Biol, 8, 616-620. PubMed id: 11427893 DOI: 10.1038/89661
Date:
30-May-01     Release date:   05-Dec-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q16854  (DGUOK_HUMAN) -  Deoxyguanosine kinase, mitochondrial
Seq:
Struc:
277 a.a.
229 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.1.113  - Deoxyguanosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + deoxyguanosine = ADP + dGMP
ATP
Bound ligand (Het Group name = ATP)
corresponds exactly
+ deoxyguanosine
= ADP
+ dGMP
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1038/89661 Nat Struct Biol 8:616-620 (2001)
PubMed id: 11427893  
 
 
Structural basis for substrate specificities of cellular deoxyribonucleoside kinases.
K.Johansson, S.Ramaswamy, C.Ljungcrantz, W.Knecht, J.Piskur, B.Munch-Petersen, S.Eriksson, H.Eklund.
 
  ABSTRACT  
 
Deoxyribonucleoside kinases phosphorylate deoxyribonucleosides and activate a number of medically important nucleoside analogs. Here we report the structure of the Drosophila deoxyribonucleoside kinase with deoxycytidine bound at the nucleoside binding site and that of the human deoxyguanosine kinase with ATP at the nucleoside substrate binding site. Compared to the human kinase, the Drosophila kinase has a wider substrate cleft, which may be responsible for the broad substrate specificity of this enzyme. The human deoxyguanosine kinase is highly specific for purine substrates; this is apparently due to the presence of Arg 118, which provides favorable hydrogen bonding interactions with the substrate. The two new structures provide an explanation for the substrate specificity of cellular deoxyribonucleoside kinases.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Initial electron density maps of dNK and dGK. a, Stereo view of the MAD phased averaged electron density map of dNK contoured at 1 . b, Stereo view of the initial eight-fold averaged electron density map of dGK contoured at 1 . The figures were made in O24 and show helices 6 and 4 at the subunit interaction area. The front of the helices face the second subunit.
Figure 3.
Figure 3. Nucleoside/nucleotide binding to dNK and dGK. a, In the crystals of dNK, deoxycytidine was present, and well-defined F[o] - F[c] density (contoured at 3 ) exists for the nucleoside substrate (right). Density for a sulfate ion and a water molecule is also present. b, The F[o] - F[c]electron density (3 ) for ATP bound to the substrate site of dGK. c, Stereo view of the binding of dC and the sulfate ion at the active site of dNK. Hydrogen bonds are red dotted lines. d, Stereo view of ATP interactions in dGK. Hydrogen bonds are red dotted lines.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 616-620) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19087190 B.Munch-Petersen (2009).
Reversible tetramerization of human TK1 to the high catalytic efficient form is induced by pyrophosphate, in addition to tripolyphosphates, or high enzyme concentration.
  FEBS J, 276, 571-580.  
20560637 S.K.Jarchow-Choy, E.Sjuvarsson, H.O.Sintim, S.Eriksson, and E.T.Kool (2009).
Nonpolar nucleoside mimics as active substrates for human thymidine kinases.
  J Am Chem Soc, 131, 5488-5494.  
18495197 A.Garcia-Maruniak, J.E.Maruniak, W.Farmerie, and D.G.Boucias (2008).
Sequence analysis of a non-classified, non-occluded DNA virus that causes salivary gland hypertrophy of Musca domestica, MdSGHV.
  Virology, 377, 184-196.  
18459168 M.J.Pérez-Pérez, E.M.Priego, A.I.Hernández, O.Familiar, M.J.Camarasa, A.Negri, F.Gago, and J.Balzarini (2008).
Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): present and future.
  Med Res Rev, 28, 797-820.  
18384378 N.E.Mikkelsen, B.Munch-Petersen, and H.Eklund (2008).
Structural studies of nucleoside analog and feedback inhibitor binding to Drosophila melanogaster multisubstrate deoxyribonucleoside kinase.
  FEBS J, 275, 2151-2160.
PDB codes: 2jj8 2vp0 2vp2 2vp4 2vp5 2vp6 2vp9 2vqs
18361501 P.Iyidogan, and S.Lutz (2008).
Systematic exploration of active site mutations on human deoxycytidine kinase substrate specificity.
  Biochemistry, 47, 4711-4720.  
18084067 E.V.Soriano, V.C.Clark, and S.E.Ealick (2007).
Structures of human deoxycytidine kinase product complexes.
  Acta Crystallogr D Biol Crystallogr, 63, 1201-1207.
PDB codes: 2qrn 2qro
17302737 L.Egeblad-Welin, Y.Sonntag, H.Eklund, and B.Munch-Petersen (2007).
Functional studies of active-site mutants from Drosophila melanogaster deoxyribonucleoside kinase. Investigations of the putative catalytic glutamate-arginine pair and of residues responsible for substrate specificity.
  FEBS J, 274, 1542-1551.
PDB code: 2jcs
17266931 M.L.Gerth, and S.Lutz (2007).
Mutagenesis of non-conserved active site residues improves the activity and narrows the specificity of human thymidine kinase 2.
  Biochem Biophys Res Commun, 354, 802-807.  
17543337 M.L.Gerth, and S.Lutz (2007).
Non-homologous recombination of deoxyribonucleoside kinases from human and Drosophila melanogaster yields human-like enzymes with novel activities.
  J Mol Biol, 370, 742-751.  
16885999 N.Solaroli, M.Johansson, J.Balzarini, and A.Karlsson (2007).
Enhanced toxicity of purine nucleoside analogs in cells expressing Drosophila melanogaster nucleoside kinase mutants.
  Gene Ther, 14, 86-92.  
17288553 U.Kosinska, C.Carnrot, M.P.Sandrini, A.R.Clausen, L.Wang, J.Piskur, S.Eriksson, and H.Eklund (2007).
Structural studies of thymidine kinases from Bacillus anthracis and Bacillus cereus provide insights into quaternary structure and conformational changes upon substrate binding.
  FEBS J, 274, 727-737.
PDB codes: 2j9r 2ja1
17581598 W.Knecht, E.Rozpedowska, C.Le Breton, M.Willer, Z.Gojkovic, M.P.Sandrini, T.Joergensen, L.Hasholt, B.Munch-Petersen, and J.Piskur (2007).
Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs.
  Gene Ther, 14, 1278-1286.  
16421443 Y.Zhang, J.A.Secrist, and S.E.Ealick (2006).
The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation.
  Acta Crystallogr D Biol Crystallogr, 62, 133-139.
PDB code: 2a7q
16008571 M.Welin, T.Skovgaard, W.Knecht, C.Zhu, D.Berenstein, B.Munch-Petersen, J.Piskur, and H.Eklund (2005).
Structural basis for the changed substrate specificity of Drosophila melanogaster deoxyribonucleoside kinase mutant N64D.
  FEBS J, 272, 3733-3742.
PDB codes: 1zm7 1zmx
15153115 H.Frederiksen, D.Berenstein, and B.Munch-Petersen (2004).
Effect of valine 106 on structure-function relation of cytosolic human thymidine kinase. Kinetic properties and oligomerization pattern of nine substitution mutants of V106.
  Eur J Biochem, 271, 2248-2256.  
15130468 N.N.Suzuki, K.Koizumi, M.Fukushima, A.Matsuda, and F.Inagaki (2004).
Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.
  Structure, 12, 751-764.
PDB codes: 1udw 1uei 1uej 1ufq 1uj2
14609716 A.R.Van Rompay, M.Johansson, and A.Karlsson (2003).
Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases.
  Pharmacol Ther, 100, 119-139.  
12694191 C.Pasti, S.Gallois-Montbrun, H.Munier-Lehmann, M.Veron, A.M.Gilles, and D.Deville-Bonne (2003).
Reaction of human UMP-CMP kinase with natural and analog substrates.
  Eur J Biochem, 270, 1784-1790.  
12808445 E.Sabini, S.Ort, C.Monnerjahn, M.Konrad, and A.Lavie (2003).
Structure of human dCK suggests strategies to improve anticancer and antiviral therapy.
  Nat Struct Biol, 10, 513-519.
PDB codes: 1p5z 1p60 1p61 1p62
14690426 J.F.Barroso, M.Elholm, and T.Flatmark (2003).
Tight binding of deoxyribonucleotide triphosphates to human thymidine kinase 2 expressed in Escherichia coli. Purification and partial characterization of its dimeric and tetrameric forms.
  Biochemistry, 42, 15158-15169.  
12493767 L.Wang, A.Saada, and S.Eriksson (2003).
Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.
  J Biol Chem, 278, 6963-6968.  
12823558 N.Solaroli, M.Bjerke, M.H.Amiri, M.Johansson, and A.Karlsson (2003).
Active site mutants of Drosophila melanogaster multisubstrate deoxyribonucleoside kinase.
  Eur J Biochem, 270, 2879-2884.  
12626708 W.Knecht, G.E.Petersen, M.P.Sandrini, L.Søndergaard, B.Munch-Petersen, and J.Piskur (2003).
Mosquito has a single multisubstrate deoxyribonucleoside kinase characterized by unique substrate specificity.
  Nucleic Acids Res, 31, 1665-1672.  
12205643 L.Salviati, S.Sacconi, M.Mancuso, D.Otaegui, P.Camaño, A.Marina, S.Rabinowitz, R.Shiffman, K.Thompson, C.M.Wilson, A.Feigenbaum, A.B.Naini, M.Hirano, E.Bonilla, S.DiMauro, and T.H.Vu (2002).
Mitochondrial DNA depletion and dGK gene mutations.
  Ann Neurol, 52, 311-317.  
11927571 W.Knecht, M.P.Sandrini, K.Johansson, H.Eklund, B.Munch-Petersen, and J.Piskur (2002).
A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines.
  EMBO J, 21, 1873-1880.  
11737647 L.Wang, J.Westberg, G.Bölske, and S.Eriksson (2001).
Novel deoxynucleoside-phosphorylating enzymes in mycoplasmas: evidence for efficient utilization of deoxynucleosides.
  Mol Microbiol, 42, 1065-1073.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.